The complexity of cancer, particularly in the establishment and growth of metastases, has hampered a comprehensive understanding of how tumor cells differ from their non-transformed counterparts. Cancer cells migrate and survive in. the peripheral bloodstream, home to specific vascular sites to initiate metastatic foci, and reprogram local stroma and induce neoangiogenesis to, permit establishment and growth of metastatic lesions. To deconvolute this complexity and to identify new pharmacological targets to inhibit metastasis initiation and growth, we will draw on our significant strengths in sophisticated micro and nanofabrication at Cornell University. This approach will enable the formation of 3D structures with precisely controlled and tunable dimensions to recapitulate and quantitatively test physicochemical determinants in the metastatic tumor microenvironment. The physical science researchers in this center bring together outstanding expertise in the most modem approaches for small scale materials processing, physical measurements and modeling. The physical science and engineering based researchers in this effort are among he world's leaders in nanobiotechnology and in the use of methods to probe life processes at the cellular and molecular level. In this application, these approaches, developed primarily for physical science experimentation, will be adapted and brought to bear on the study of cancer, with an emphasis on dissecting the molecular mechanisms that regulate circulating tumor cell migration, adhesion and the establishment of metastatic foci via interactions with tissue stroma and the nascent tumor vasculature. Working together with leading cancer investigators at Weill Medical College Cancer Center and the University of Buffalo, this team will inform a new fundamental level of understanding of tumor cells, including patient-derived circulating tumor cells, and their interaction with defined microenvironments. Rather than focusing on candidate genes for intervention, these studies will use unbiased gene and pathway discovery approaches to facilitate prediction of viable pathways for novel interventions in cancer metastasis. Cross-training of junior investigators and faculty across physical science and cancer biology disciplines will be emphasized, to educate a new generation of scientist to explore the scientific basis of cancer. New core facilities, including selected cell epigenomic analysis, and newly developed methods in micro and nanofabrication be made available to researchers of Physical Sciences Oncology Centers to enrich collaborations and disseminate technological advances throughout the network. By this approach the impact of this research should be felt far more widely than ordinary individual investigator projects.